Although HIV RNA can be detected in saliva, the difficulty in culturing HIV from oral presence of HIV inhibitors in saliva strongly suggest that saliva is not a source of infectious virus and that transmission through the oral route is, at best, inefficient. Recent studies, however, have raised doubts about this assumption. Thus, macaques may become orally infected with SIV; moreover, human seroconversion may occur under conditions where the only risk is oral-genital contact. We reported that most seronegative individuals secrete salivary proteins which specifically block the infectivity of HIV-1 in vitro. This inhibition is seen with both laboratory strains and clinical HIV isolates and is specific for HIV-1. Thus, our studies support the notion that salivary proteins exert a specific inhibitory effect on HIV-1 infection. We recently identified salivary agglutinin (SAG) as a key protein in saliva that inhibits HIV infectivity. Our hypothesis is that SAG, and perhaps other salivary proteins with anti-HIV-1 activity, are responsible for modulating HIV transmission and acquisition by the oral route. To test this hypothesis, we propose: 1. To identify the active domains of salivary agglutinin (SAG) involved in the inhibition of HIV-1 infection. 2. To examine the interaction of SAG with and to ascertain if this interaction results in shedding of gp120 from the virus. 3. To determine the mechanism by which salivary proteins inhibit HIV infectivity using in vitro models of oral infection. 4. To define the significance of anti-HIV proteins in saliva obtained from HIV-seropositive donors.